Mechanistic insight into the dominant mode of the Parkinson's disease-associated G2019S LRRK2 mutation

Berta Luzón-Toro, Elena Rubio de la Torre, Asunción Delgado, Jordi Pérez-Tur, Sabine Hilfiker

Research output: Contribution to journalArticlepeer-review

101 Scopus citations


Pathogenic mutations in the leucine-rich repeat kinase-2 (LRRK2) gene cause autosomal-dominant and certain cases of sporadic Parkinson's disease (PD). The G2019S substitution in LRRK2 is the most common genetic determinant of PD identified so far, and maps to a specific region of the kinase domain called the activation segment. Here, we show that autophosphorylation of LRRK2 is an intermolecular reaction and targets two residues within the activation segment. The prominent pathogenic G2019S mutation in LRRK2 results in altered autophosphorylation, and increased autophosphorylation and substrate phosphorylation, through a process that seems to involve reorganization of the activation segment. Our results suggest a molecular mechanistic explanation for how the G2019S mutation enhances the catalytic activity of LRRK2, thereby leading to pathogenicity. These findings have important implications for therapeutic strategies in PD.

Original languageEnglish (US)
Pages (from-to)2031-2039
Number of pages9
JournalHuman molecular genetics
Issue number17
StatePublished - Sep 1 2007
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Genetics(clinical)
  • Genetics
  • Molecular Biology


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